Persistent changes in gene expression may mediate many alcohol effects including reward learning, tolerance and dependence, suggesting that agents effective at changing alcohol-induced gene expression should be considered as therapeutic agents. Drugs targeting gene expression through inhibition of enzymes that regulate chromatin structure (epigenetic drugs) have been widely used in cancer research and recently emerged as potential therapeutics for neurodegenerative disorders and drug addiction. The main goals of this project are: 1) to identify epigenetic drugs that affect alcohol reward through testing their effects on alcohol consumption and conditioned place preference (CPP) and 2) to investigate the effects of selected epigenetic drugs on gene expression and cellular physiology in the reward pathway including ventral tegmental area (VTA) and the nucleus accumbens (NA). The overall hypothesis is that some epigenetic drugs will reduce the rewarding properties of alcohol through changes in gene expression and cellular physiology in the reward pathway. To address this research problem, we will use a combination of pharmacological, behavioral, genomic and electrophysiological approaches. Alcohol will be delivered via voluntary consumption using a mouse model of binge drinking or via systemic injections to produce CPP. Epigenetic drugs will be delivered via systemic injections prior to alcohol. We will use laser capture microdissections to dissect VTA and NA. We will measure global gene expression in these regions after different combinations of epigenetic drugs, vehicle and alcohol. VTA dopamine neurons will be tested using electrophysiological techniques in parallel with gene expression. Microarray results will be validated using qRT-PCR and epigenetic assays. Integration of electrophysiological and gene expression data will elucidate the drug's mechanisms of action and identify novel targets for drug development. This research will provide initial mechanistic evidence for the therapeutic potential of epigenetic drugs in treating alcohol addiction.